Structure of a Ca2+-myristoyl switch protein that controls activation of a phosphatidylinositol 4-kinase in fission yeast

Neuronal calcium sensor (NCS) proteins transduce Ca2+ signals and are highly conserved from yeast to humans. We determined NMR structures of the NCS-1 homolog from fission yeast (Ncs1), which activates a phosphatidylinositol 4-kinase. Ncs1 contains an α-NH2-linked myristoyl group on a long N-terminal arm and four EF-hand motifs, three of which bind Ca2+, assembled into a compact structure. In Ca2+-free Ncs1, the N-terminal arm positions the fatty acyl chain inside a cavity near the C terminus. The C14 end of the myristate is surrounded by residues in the protein core, whereas its amide-linked (C1) end is flanked by residues at the protein surface. In Ca2+-bound Ncs1, the myristoyl group is extruded (Ca2+-myristoyl switch), exposing a prominent patch of hydrophobic residues that specifically contact phosphatidylinositol 4-kinase. The location of the buried myristate and structure of Ca2+-free Ncs1 are quite different from those in other NCS proteins. Thus, a unique remodeling of each NCS protein by its myristoyl group, and Ca2+-dependent unmasking of different residues, may explain how each family member recognizes distinct target proteins.     

The Dopamine D1-D2 Receptor Heteromer Localizes in Dynorphin/Enkephalin Neurons: INCREASED HIGH AFFINITY STATE FOLLOWING AMPHETAMINE AND IN SCHIZOPHRENIA*

The distribution and function of neurons coexpressing the dopamine D1 and D2 receptors in the basal ganglia and mesolimbic system are unknown. We found a subset of medium spiny neurons coexpressing D1 and D2 receptors in varying densities throughout the basal ganglia, with the highest incidence in nucleus accumbens and globus pallidus and the lowest incidence in caudate putamen. These receptors formed D1-D2 receptor heteromers that were localized to cell bodies and presynaptic terminals. In rats, selective activation of D1-D2 heteromers increased grooming behavior and attenuated AMPA receptor GluR1 phosphorylation by calcium/calmodulin kinase IIα in nucleus accumbens, implying a role in reward pathways. D1-D2 heteromer sensitivity and functional activity was up-regulated in rat striatum by chronic amphetamine treatment and in globus pallidus from schizophrenia patients, indicating that the dopamine D1-D2 heteromer may contribute to psychopathologies of drug abuse, schizophrenia, or other disorders involving elevated dopamine transmission.     

早期高压氧联合去骨瓣减压治疗重型颅脑损伤的疗效及对患者神经功能、炎性因子的影响

摘要 目的：分析早期高压氧联合去骨瓣减压治疗重型颅脑损伤的疗效及对患者神经功能、炎性因子的影响。方法：选择我院自2018年1月至2021年10月接诊的106例重型颅脑损伤患者,随机分为对照组和观察组,各53例。两组均予以常规对症支持治疗,在此基础上,对照组采取去骨瓣减压治疗,观察组采取早期高压氧联合去骨瓣减压治疗。随访3个月,比较两组治疗前后的脑代谢指标、Fugl-Meyer运动功能评分、神经功能指标、炎性因子、严重并发症发生率及近期疗效。结果：观察组治疗后脑氧摄取率（CEO₂）、混合静脉血氧饱和度（SVO₂）均高于对照组（P＜0.05）;观察组治疗后上肢、下肢及总体Fugl-Meyer运动功能评分均高于对照组（P＜0.05）;观察组治疗后血清脑源性神经营养因子（BDNF）、神经元特异性烯醇化酶（NSE）、S100β蛋白、胶质纤维酸性蛋白（GFAP）水平均低于对照组,神经生长因子（NGF）水平高于对照组（P＜0.05）;观察组治疗后血清C反应蛋白（CRP）、白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）均低于对照组（P＜0.05）;观察组严重并发症发生率低于对照组,预后良好率高于对照组（P＜0.05）。结论：早期高压氧联合去骨瓣减压治疗重型颅脑损伤的疗效显著,能够有效优化患者神经功能,抑制炎症反应,促进肢体运动功能恢复,进而改善预后,值得临床予以重视。     

前后联合入路微创治疗合并神经损伤的不稳定骶骨骨折

目的:探讨前后联合入路锁定加压钢板(LCP)微创治疗合并神经损伤的骶骨不稳定骨折的效果。方法:前后联合入路按照杜明奎等方法[1]采用LCP固定治疗合并神经损伤的不稳定骶骨骨折患者5例:L5神经根损伤2例,骶丛神经损伤3例。前方入路暴露骨盆前环重建钢板固定,后方入路经皮下锁定加压钢板骨折复位固定术,椎管探查减压以MRI显示有无神经压迫为据。结果:5例均获随访,时间3～20(14.8±7.2)个月。2例L5神经根损伤和3例骶丛神经损伤者Frankel分级由C级恢复至E级,术后功能根据Matta评分标准评定:优3例,良2例。结论:前后联合入路LCP微创治疗合并神经损伤的骶骨不稳定骨折是一种简单微创有效的方法,值得临床推广。     

Presenilin-2 polymorphisms and risk of sporadic AD: Evidence from a meta-analysis

Association studies of presenilin-2 (PSEN2) polymorphisms and sporadic Alzheimer's disease (AD) have yielded inconsistent results, possibly because single studies often lack sufficient statistical power. In this study, we performed a meta-analysis to evaluate the association of the two most extensively studied PSEN2 polymorphisms, rs8383 and 5′indel, with the risk of sporadic AD. We systematically reviewed relevant studies retrieved by Medline, Pubmed, Embase, AlzGene, and CNKI. Data were analyzed using the Stata (v11.0) software package. The fixed effects model or random-effects model were applied depending on between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's funnel plots. Overall, the meta-analysis included 6 case–control studies for each polymorphism with 2186 confirmed AD cases and 2507 healthy controls in total. Analysis suggested a significant association between SNP rs8383 polymorphism and AD risk with no evidence of between-study heterogeneity or publication bias. In contrast, we found no evidence for an association between the 5′indel polymorphism and AD risk. Further stratified analyses by apolipoprotein ε4 status or ethnicity also failed to reveal a statistically significant association between the 5′indel polymorphism of PSEN2 and AD risk. Our analysis supports the hypothesis that the PSEN2 rs8383 polymorphism is associated with an enlarged risk of sporadic AD. However, larger scale association studies are necessary to further validate the association of PSEN2 polymorphisms with sporadic AD risk and to define potential gene–gene interactions.     

An overview on the correlation of neurological disorders with cardiovascular disease

Neurological disorders (NDs) are one of the leading causes of death especially in the developed countries. Among those NDs, Alzheimer’s disease (AD) and Parkinson disease (PD) are heading the table. There have been several reports in the scientific literatures which suggest the linkage between cardiovascular disorders (CVDs) and NDs. In the present communication, we have tried to compile NDs (AD and PD) association with CVDs reported in the literature. Based on the available scientific literature, we believe that further comprehensive study needs to be done to elucidate the molecular linking points associated with the above mentioned disorders.Abbreviations: AD, Alzheimer’s disease, Aβ, β amyloid, PD, Parkinson disease, l-DOPA, l-dihydroxyphenylalanine, LBs, Lewy bodies, DA, dopamine, APP, amyloid precursor protein, CVD, cardiovascular disease     

Serum S100B is a useful surrogate marker for long-term outcomes in photochemically-induced thrombotic stroke rat models

In recent years, serum S100B has been used as a secondary endpoint in some clinical trials, in which serum S100B has successfully indicated the benefits or harm done by the tested agents. Compared to clinical stroke studies, few experimental stroke studies report using serum S100B as a surrogate marker for estimating the long-term effects of neuroprotectants. This study sought to observe serum S100B kinetics in PIT stroke models and to clarify the association between serum S100B and both final infarct volumes and long-term neurological outcomes. Furthermore, to demonstrate that early elevations in serum S100B reflect successful neuroprotective treatment, a pharmacological study was performed with a non-competitive NMDA glutamate receptor antagonist, MK-801. Serum S100B levels were significantly elevated after PIT stroke, reaching peak values 48 h after the onset and declining thereafter. Single measurements of serum S100B as early as 48 h after PIT stroke correlated significantly with final infarct volumes and long-term neurological outcomes. Elevated serum S100B was significantly attenuated by MK-801, correlating significantly with long-term beneficial effects of MK-801 on infarct volumes and neurological outcomes. Our results showed that single measurements of serum S100B 48 h after PIT stroke would serve as an early and simple surrogate marker for long-term evaluation of histological and neurological outcomes in PIT stroke rat models.     

Longitudinal association between serum uric acid levels and multiterritorial atherosclerosis

Multiterritorial atherosclerosis has dramatically increased annual risk of adverse cardiovascular events than atherosclerotic disease with single‐artery affected. Serum uric acid (SUA) is an important predictor of stroke and atherosclerosis; however, which is supported by few direct evidence based on cohort studies. A prospective cohort study including 2644 North Chinese adults aged ≥40 years was performed in 2010‐2012 to investigate the association between SUA and multiterritorial vascular stenosis. Hyperuricaemia was defined as SUA levels >6 and >7 mg/dL for males and females, respectively. All participants underwent twice transcranial Doppler (TCD) and bilateral carotid duplex ultrasound to evaluate intracranial artery stenosis (ICAS) and extracranial arterial stenosis (ECAS) and peripheral arterial disease (PAD) was determined by ankle‐brachial index (ABI) on January 2010 and January 2012 based on regular health check‐ups. The cumulative incidence of vascular stenosis was significantly higher in subjects with hyperuricaemia than in those without hyperuricaemia (54.1% vs. 34.7%, P < 0.001). The adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for new on‐set vascular stenosis due to hyperuricaemia and a 1‐mg/dL change in SUA level were 1.75 (1.32‐2.31) and 1.29 (1.21‐1.38), respectively. Furthermore, in the gender‐stratified analysis, the association between SUA levels and ICAS was statistically significant in males (OR: 2.02; 95% CI: 1.18‐3.46), but not females (OR: 0.85, 95% CI: 0.41‐1.76, P for interaction: 0.026).     

灯盏花素注射液联合依达拉奉注射液对未溶栓急性脑梗死患者神经功能、脑血流动力学和血清炎症细胞因子的影响

摘要 目的：观察灯盏花素注射液联合依达拉奉注射液对未溶栓急性脑梗死（ACI）患者神经功能、脑血流动力学和血清炎症细胞因子的影响。方法：选取2020年4月~2022年1月来我院接受治疗的未溶栓ACI患者82例。采用随机数字表法将患者分为对照组（依达拉奉注射液治疗,41例）和实验组（灯盏花素注射液联合依达拉奉注射液治疗,41例）。观察两组临床疗效,神经功能、脑血流动力学和血清炎症细胞因子的变化,记录两组不良反应情况。结果：实验组的临床总有效率为90.24%,高于对照组的68.29%,差异有统计学意义（P<0.05）。实验组治疗7d后美国国立卫生研究院卒中量表（NIHSS）评分低于对照组,日常生活活动能力（ADL）评分高于对照组P<0.05）。实验组治疗7d后脑血流平均血流速度（Vm）、收缩期峰值血流速度（Vs）、舒张期血流速度（Vd）高于对照组（P<0.05）。实验组治疗7 d后白介素-6（IL-6）、超敏C反应蛋白（hs-CRP）水平低于对照组（P<0.05）。两组均未出现严重的不良反应。结论：依达拉奉注射液联合灯盏花素注射液治疗未溶栓ACI患者,可调节脑血流动力学,减轻神经功能损伤,降低血清炎症细胞因子,且具有较好的安全性。     

The Impact of COVID-19 On Comorbidities: A Review Of Recent Updates For Combating It

Coronavirus disease is caused by the SARS-CoV-2 virus. The virus first appeared in Wuhan (China) in December 2019 and has spread globally. Till now, it affected 269 million people with 5.3 million deaths in 224 countries and territories. With the emergence of variants like Omicron, the COVID-19 cases grew exponentially, with thousands of deaths. The general symptoms of COVID-19 include fever, sore throat, cough, lung infections, and, in severe cases, acute respiratory distress syndrome, sepsis, and death. SARS-CoV-2 predominantly affects the lung, but it can also affect other organs such as the brain, heart, and gastrointestinal system. It is observed that 75 % of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. The most common reported comorbidities are hypertension, NDs, diabetes, cancer, endothelial dysfunction, and CVDs. Moreover, older and pre-existing polypharmacy patients have worsened COVID-19 associated complications. SARS-CoV-2 also results in the hypercoagulability issues like gangrene, stroke, pulmonary embolism, and other associated complications. This review aims to provide the latest information on the impact of the COVID-19 on pre-existing comorbidities such as CVDs, NDs, COPD, and other complications. This review will help us to understand the current scenario of COVID-19 and comorbidities; thus, it will play an important role in the management and decision-making efforts to tackle such complications.